19-Hydroxy-19-methyl-6-hydroxy-7a-homo-PGI1 compounds

ABSTRACT

The present invention provides novel 19-hydroxy-19-methyl-6-hydroxy-7a-homo-PGI 1  compounds which are useful for pharmacological purposes, e.g., anti-asthmatic indications.

CROSS REFERENCE TO RELATED APPLICATION

The present invention is a divisional application of U.S. Ser. No.054,720, filed July 5, 1979, now U.S. Pat. No. 4,225,507.

BACKGROUND OF THE INVENTION

The present invention provides novel prostacyclin analogs. Particularly,the present invention relates to prostacyclin analogs substituted at theC-19 position by hydroxy.

Particularly, the present invention relates to19-hydroxy-19-methyl-6-hydroxy-7a-homo-PGI₁ compounds. The novelprostacyclin analogs are useful for pharmacological purposes, e.g., asanti-asthmatic agents. The preparation and use of these compounds isincorporated here by reference from U.S. Pat. No. 4,225,507.

PRIOR ART

For background on prostacyclin, see for example R. A. Johnson, et al.,Prostaglandins 12, 915-928 (1976) and R. A. Johnson, et. al., J. Am.Chem. Soc. 100, 7690-7704 (1978), and, as to pharmacological activity,the references cited therein. For analogs of prostacyclin, see, forexample, J. Fried, et al., Proc. Natl. Acad. Sci. U.S.A. 74, 2199-2203,K. C. Nicolaou, et al., J.C.S. Chem. Comm. 1977, 331-332, N. A. Nelson,J. Am. Chem. Soc. 99, 7362-7363 (1977), and K. Kojima, et al., Tetra.Letters, 1978, (1977), and K. Kojima, et al., Tetra. Letters, 1978,3743-3746. Regarding the nomenclature for analogs of PGI₂, see R. A.Johnson, et al., Prostaglandins 15, 737-740 (1978).

SUMMARY OF THE INVENTION

The present invention particularly provides

a prostacyclin-type compound of the formula ##STR1##

wherein A₁ is --O-- (oxa) and E₂ is --CH₂ CH₂ --;

wherein L₂ is

(1) --(CH₂)_(j) --, wherein j is one to 4, inclusive,

(2) --(CH₂)_(q) --CF₂ --, wherein q is one, 2, or 3; or

(3) --CH═CH--;

wherein M₁ is ##STR2##

wherein Q is oxo, α-H:β-H, α-OH:β-R₄, or α-R₄ :β-OH,

wherein R₄ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,wherein R₁ is

(1) --COOR₃,

(2) --CH₂ OH,

(3) --CH₂ N(R₇)(R₈),

(4) --CO--N(R₇)(R₈),

(5) --CO--NH--SO₂ --R₁₅, or

(6) tetrazolyl,

wherein R₃ is

(a) hydrogen,

(b) alkyl of one to 12 carbon atoms, inclusive,

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(d) aralkyl of 7 to 12 carbon atoms, inclusive,

(e) phenyl,

(f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of oneto 3 carbon atoms, inclusive;

(g) --(Ph)--CO--CH₃,

(h) --(p-Ph)--NH--CO--(p-Ph)--NH--CO--CH₃,

(i) --(p-Ph)--NH--CO--(p-Ph),

(j) --(p-Ph)--NH--CO--CH₃,

(k) --(p-Ph)--NH--CO--NH₂,

(l) --(p-Ph)--CH═N--NH--CO--NH₂,

(m) β-naphthyl,

(n) --CH₂ --CO--R₁₆,

wherein --(Ph)-- is inter-phenylene and --(p-Ph) is inter-para-phenyleneor para-phenyl;

wherein R₁₆ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl,p-benzamidophenyl, or 2-naphthyl, or

(o) a pharmacologically acceptable cation; wherein R₇ and R₈ arehydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl,being the same or different, and wherein R₁₅ is hydrogen, alkyl of oneto 12 carbon atoms, inclusive, phenyl, phenyl-substituted with one, 2,or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive, orphenyl substituted with hydroxycarbonyl or alkoxycarbonyl of 2 to 4carbon atoms, inclusive,

wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl,

wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or fluoro, being the same or different, with the proviso thatone of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro,and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --.

I claim:
 1. A prostacyclin-type compound of the formula ##STR3## whereinA₁ is --O-- (oxa) and E₂ is --CH₂ CH₂ --; wherein L₂ is(1) --(CH₂)_(j)--, wherein j is one to 4, inclusive, (2) --(CH₂)_(q) --CF₂ --, whereinq is one, 2, or 3; or (3) --CH═CH--; wherein M₁ is ##STR4## wherein Q isoxo, α-H:β-H, α-OH:β-R₄, or α-R₄ :β-OH, wherein R₄ is hydrogen or alkylof one to 4 carbon atoms, inclusive, wherein R₁ is(1) --COOR₃, (2) --CH₂OH, (3) --CH₂ N(R₇)(R₈), (4) --CO--N(R₇)(R₈), (5) --CO--NH--SO₂ --R₁₅,or (6) tetrazolyl, wherein R₃ is(a) hydrogen, (b) alkyl of one to 12carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms,inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl,(f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of oneto 3 carbon atoms, inclusive; (g) --(Ph)--CO--CH₃, (h)--(p-Ph)--NH--CO--(p-Ph)--NH--CO--CH₃, (i) --(p-Ph)--NH--CO--(p-Ph), (j)--(p-Ph)--NH--CO--CH₃, (k) --(p-Ph)--NH--CO--NH₂, (l)--(p-Ph)--CH═N--NH--CO--NH₂, (m) β-naphthyl, (n) --CH₂ --CO--R₁₆,wherein --(Ph)-- is inter-phenylene and --(p-Ph) is inter-para-phenyleneor para-phenyl; wherein R₁₆ is phenyl, p-bromophenyl, p-bisphenylyl,p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or(o) apharmacologically acceptable cation; wherein R₇ and R₈ are hydrogen,alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being thesame or different, and wherein R₁₅ is hydrogen, alkyl of one to 12carbon atoms, inclusive, phenyl, phenyl-substituted with one, 2, or 3chloro or alkyl groups of one to 3 carbon atoms, inclusive, or phenylsubstituted with hydroxycarbonyl or alkoxycarbonyl of 2 to 4 carbonatoms, inclusive, wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl,wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or fluoro, being the same or different, with the proviso thatone of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro,and wherein X is(1) trans--CH═CH--, (2) cis--CH═CH--, (3) --C.tbd.C--,or (4) --CH₂ CH₂ --.
 2. A compound according to claim 1, wherein R₁ is--CH₂ OH.